Phase I trial of BAY 73-4506, a kinase inhibitor that targets oncogenic and angiogenic kinases, in patients with advanced solid tumors

B85 Background: BAY 73-4506 is an orally active kinase inhibitor that targets both the tumor and its vasculature. BAY 73-4506 is a potent inhibitor of the oncogenic RTK (KIT, RET, PDGFR), angiogenic RTK (VEGFR-1, -2 and -3 and PDGFR-β) and serine/threonine kinases (p38MAPK and RAF). In preclinical cancer xenograft models, BAY 73-4506 demonstrated a broad spectrum anti-tumor activity.
 Methods: The phase I study described here is an ongoing dose-escalation trial investigating the safety, pharmacokinetic (PK), and pharmacodynamic profile of BAY 73-4506 given orally in 21 days on/7 days off cycles, until discontinuation due to toxicity or tumor progression. PK is assessed on days 1 and 21 of cycle 1. Pharmacodynamic markers, including dynamic contrast-enhanced MRI (DCE-MRI), circulating soluble VEGFR-2 (sVEGFR-2) and plasma VEGF level, are assessed at each cycle. Tumor response is evaluated per RECIST criteria.
 Results : 41 patients with solid tumors and progressive disease were enrolled in this trial and treated with BAY 73-4506 at doses of 10 mg to 220 mg once daily. Most frequent tumor types (>5%) included colorectal carcinoma (n=11, 27%), malignant melanoma (n=5, 12%), renal cell carcinoma (n=4, 10%), and soft tissue sarcoma (n=4, 10%). The median treatment duration was 41 medication days (min. 1, max. 375). Commonly reported drug-related adverse events (AEs) (>10% of pts) were hoarseness (n=21, 51%), dermatological toxicities (n=17, 41%, CTC grade 3 in 5 pts 12%), mucositis (n=11, 27%), fatigue (n=8, 20%, CTC grade 3 in 1 pt 2%), diarrhea (n=8, 20%), anorexia (n=7, 17%, CTC grade 3 in 1 pt 2%), hypertension (n=6, 15%, CTC grade 3 in 1 pt 2%), and weight loss (n=5, 12%). Treatment-related AEs leading to dose reduction, interruption or discontinuation were dermatological toxicities (n=6, 15%), fever without documented infection (n=2, 5%), leucopenia / thrombopenia (n=1, 2%), diarrhea (n=1, 2%), and fatigue (n=1, 2%). BAY 73-4506 exposure increased with dose up to 120 mg reaching a plateau at higher doses; the AUC target exposure level of 13 mg*h/L (from preclinical xenograft models) was reached at 30 mg. The major metabolites of BAY 73-4506 (active in vitro ) showed dose-dependent increases in exposure up to 220 mg and reached similar AUC(0-24) ss as the parent drug at 220 mg. Two patients (RCC and osteosarcoma) out of 30 evaluable patients achieved RECIST partial response (7%). Seventeen patients (57%) had stable disease at least 7 weeks after start of treatment and 7 of these patients (23%) had stable disease for more than 15 weeks. Pharmacodynamic parameters (decrease in sVEGFR-2 level, decrease in iAUC60s of Gd-DTPA by DCE-MRI) correlated with drug exposure.
 Conclusions: BAY 73-4506 was well tolerated when given at doses up to 160 mg once daily. The toxicity evaluation with the 220 mg dose is ongoing with additional patients being enrolled. In nineteen out of 30 evaluable patients (63%) antitumor activity has been demonstrated. Optimal dose and regimen are under evaluation in preparation for phase II trials.